What are the development directions for anticancer drugs targeting Nectin-4 in more than 20 clinical studies around the world?

Text|Pharmaceutical Mission Hills

A brand-new drug target is entering people's field of vision and is well known by more people in the industry.
It is the membrane protein adhesion molecule Nectin-4
.

This is because a number of drugs under development that target Nectin-4 have recently ushered in important progress

With the vigorous development of new technologies and new discoveries, new targets and their application potential are always attracting attention
.

So, what is Nectin-4? How is it related to cancer? What is the current status of research and development of drugs targeting Nectin-4 in the world?

Nectin-4 and the occurrence of cancer

Nectin-4 and the occurrence of cancer

The full name of Nectin-4 is Nectin cell adhesion molecule 4, which belongs to the Nectin family of Ig superfamily proteins
.

It is a type I membrane protein that is overexpressed in a variety of tumor cells, including urothelial cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma and bladder cancer

Studies have found that Nectin-4 promotes tumor cell proliferation, differentiation, migration, invasion, etc.
by activating the PI3K/Akt pathway, and is considered to play an important role in the occurrence and metastasis of cancer
.

It is based on these research backgrounds that drug research for this target has also emerged

Up to now, in the global field, there have been successful cases of drug development targeting Nectin-4, which is the world's first Nectin-4 antibody conjugate drug enfortumab vedotin approved by the US FDA for the treatment of urothelium Cancer patients
.

Checking the ClinicalTrails website shows that there are currently more than 20 clinical research projects related to Nectin-4 target drugs in the world
.

Although compared with other popular targets, this direction is still a little lonely, but from the perspective of continuous new research, the development potential of Nectin-4 target is gradually being highlighted

The first ADC drug targeting Nectin-4 was born

The first ADC drug targeting Nectin-4 was born

Enfortumab vedotin is a "first-in-class" new drug jointly developed by Astellas and Seagen (formerly known as Seattle Genetics).
It is a dipeptide linking anti-Nectin-4 antibody and microtubule disrupting agent MMAE The antibody is conjugated to the drug generated by the linking of the daughters
.

Its anti-cancer mechanism is that when it binds to Nectin-4 on the surface of tumor cells, it enters the cell through endocytosis of tumor cells, and the dipeptide linker is cleaved by intracellular proteolytic enzymes to release the toxin MMAE , So as to achieve targeted killing of tumors

The preclinical and clinical studies that have been carried out have confirmed the therapeutic effect of enfortumab vedotin in tumors
.

At the 2019 American Society of Clinical Oncology (ASCO) annual meeting, it "stunned" the audience with its treatment results in advanced bladder cancer: in 125 patients, it brought a 44% objective response rate (ORR) ), where the complete response rate (CR) is 12%

Based on these positive results, the FDA approved the marketing of enfortumab vedotin in December 2019 for the treatment of patients with locally advanced or metastatic urothelial cancer who have received platinum-based chemotherapy and PD-1/PD-L1 inhibitors.

.

This approval is nearly 4 months ahead of the scheduled PDUFA date

As of September 2020, enfortumab vedotin has reached the primary endpoint of overall survival in a phase 3 clinical trial for the treatment of patients with locally advanced or metastatic urothelial cancer
.

It reduces the patient’s risk of death by 30%, and also significantly improves the patient’s progression-free survival, reducing the risk of disease progression or death by 39%
.
As a representative of a new model of cancer treatment, this therapy brings new treatment options to patients with advanced urothelial cancer who have undergone chemotherapy and immunotherapy
.

In China, the clinical trial application of enfortumab vedotin for injection declared by Astellas obtained two implied licenses from the Center for Drug Evaluation (CDE) of the State Drug Administration of China in December 2020.
It is intended to be developed for use in locally advanced or Metastatic urothelial carcinoma
.

A few days ago, another Nectin-4 targeted ADC drug developed by a Chinese company has also entered people's field of vision
.
The clinical trial application (IND) of 9MW2821 developed by Maiwei Biotechnology was accepted by CDE
.
Public information shows that 9MW2821 shows good tumor suppression effects in a variety of animal tumor models, and its safety data in cynomolgus monkeys and mice shows a better treatment window
.

Targeting Nectin-4, what new types of drugs are still being developed?

Targeting Nectin-4, what new types of drugs are still being developed?

With the approval of the world's first Nectin-4 targeting ADC drug, this target has also been recognized by more drug researchers
.
In addition to ADC drugs, there are also some new types of drugs targeting Nectin-4, including Bicycle Toxin Conjugate (BTC), bispecific bicyclic peptides, CAR-T cell therapy products, and related combination therapies
.

Among them, the more concerned is the research product BT8009 that is being developed by Bicycle Therapeutics.
It is a BTC drug targeting Nectin-4.
It is currently in phase 1/2 clinical trials and the trial is expressed in Nectin-4.
Related to patients with advanced solid tumors
.

Image source: Bicycle Therapeutics' official website

As a new biotechnologist, Bicycle Therapeutics is developing a new type of drug-bicyclic peptides, also known as Bicycles
.
It is reported that the molecular weight of these drugs is 50-100 times smaller than that of typical antibody-conjugated drugs.
They are expected to penetrate tumors completely and have advantages in tumor antigen targeting
.
Moreover, BT8009 has demonstrated better anti-tumor activity in preclinical studies
.

Dr.
Kevin Lee, CEO of Bicycle Therapeutics, once stated in a press release that BT8009 is one of a new class of tumor-targeted drugs, which represents the next generation of solid tumor treatments
.

In addition, the company also has another bispecific bicyclic peptide research project targeting Nectin-4 and CD137 (also known as 4-1BB)
.

Image source: Bicycle Therapeutics' official website

In addition to single-agent therapy, Nectin-4 targeted therapy is also expected to exert its potential in combination therapy
.
Take Astellas’ enfortumab vedotin as an example.
According to the information query of ClinicalTrails, the drug is currently exploring the combination of different PD-1/PD-L1 immunotherapies.
On the one hand, it uses small molecule toxins to target Nectin- 4 Highly expressed tumor cells, on the other hand, destroy tumor cells by activating T cells
.

In these combined treatment studies, there are not only small molecule drugs such as cabozantinib and sitravatinib, but also anti-PD-1 antibody pembrolizumab and anti-PD-L1 antibody duvalizumab.
Anti-durvalumab, CTLA-4 inhibitor tremelimumab, ADC drug sacituzumab govitecan, etc.
The indications mainly involve bladder cancer, urothelial cancer and other solid tumors
.

It is worth mentioning that the combination therapy consisting of enfortumab vedotin and PD-1 inhibitor pembrolizumab has been granted a breakthrough therapy designation by the FDA as a first-line therapy for newly treated patients with locally advanced or metastatic urothelial cancer
.

Take the BTC drug BT8009 as an example.
In addition to monotherapy, Bicycle Therapeutics also plans to evaluate the efficacy and safety of BT8009 combined with PD-1 inhibitor nivolumab in clinical trials
.

In short, Nectin-4 is already a well-proven tumor antigen, especially the birth of the first ADC drug targeting Nectin-4, which proves that it is an effective target for tumor drug development, and it is also an effective target for the development of tumor drugs.
The development of other new drug classes has identified the basis
.

Although the number of research and development pipelines targeting Nectin-4 has not been reported so far
.
However, with the further advancement of related research, it is expected that in the future, more antibody drugs, ADC drugs and other new drugs targeting Nectin-4 will enter clinical research and shine in more cancer treatment fields
.

references:

[1] The first domestic company’s application for a new ADC clinical trial targeting Nectin-4 was accepted by NMPA.
Retrieved Aug 10, 2021, from https://mp.
weixin.
qq.
com/s/PRImjGWGEJwoLC0h77KGDA

[2] The official website of the Center for Drug Evaluation of the State Drug Administration of China.
Retrieved Agu 20, 2021, from http://#

[3] Research progress in the application of Nectin-4 target in the field of tumor therapy
.
"Chinese and Foreign Medical Research" Volume 18, Issue 36 (Total Issue 476) December 2020

[4]Bicycle Therapeutics Announces First Patient Dosed in Phase I/II Trial of Bicycle® Toxin Conjugate BT8009 in Patients with Advanced Solid Tumors.
Retrieved Sep 10, 2020, From https://investors.
bicycletherapeutics.
com/news-releases/news -release-details/bicycle-therapeutics-announces-first-patient-dosed-phase-iii-0